Haematological malignancies cancer susceptibility

Gene: MBD4

Green List (high evidence)

The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.

Created: 30 Jan 2023, 11:21 a.m. | Last Modified: 30 Jan 2023, 11:21 a.m.

Panel Version: 3.3

Re-tagging on this panel following a new Green expert review by Dr Claire Palles on a different GMS panel (R347, R211) to ensure that if the decision is made to include the gene, all panels are appropriately updated.

Loss of MBD4 leads to an accumulation of somatic CpG>TpG transitions, consistent with MBD4 function which involves repair of G:T mismatches resulting from deamination of 5'-methylcytosine. Germline MBD4 inactivation can therefore lead to somatic variation (i.e. CpG>TpG) in well-known cancer driver genes, in turn conferring cancer susceptibility. Although MBD4 itself does not directly drive oncogenesis, evidence suggests it may modify disease risk as shown by multiple cases reported in literature with this distinctive mutational signature.

Created: 5 Jul 2022, 3:23 p.m. | Last Modified: 16 Nov 2022, 10:47 a.m.

Panel Version: 2.38

Palles et al. 2022 (PMID: 35460607) reported on 5 individuals from 4 families with biallelic MBD4 variants who had a personal and/or family history of adenomatous colorectal polyposis (5/5), AML (1/5 personal, 2 family), and uveal melanoma (2/5 personal). Consistent with previous studies, MBD4-deficient colorectal adenomas showed a significantly increased mutational burden compared to sporadic colorectal tumours, which were mostly attributable to an excess of CpG>TpG transitions.

Created: 5 Jul 2022, 3:17 p.m. | Last Modified: 5 Jul 2022, 3:19 p.m.

Panel Version: 2.33

After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed.

Created: 3 Mar 2022, 10:30 a.m. | Last Modified: 3 Mar 2022, 10:30 a.m.

Panel Version: 2.23

Comment on list classification: New gene added by Kiran Tawana (Addenbrooke's Hospital, Cambridge) with a Green expert review rating.

Studies indicate that while germline MBD4 deficiency alone does not drive malignant transformation, it may alter the mutational spectrum and in turn modify susceptibility and predisposition to cancers such as AML.

Therefore, rating this gene as Amber with the recommendation of review by the GMS team with regards to whether such alterations are within the scope of this panel (added 'for-review' tag)

Created: 2 Feb 2021, 5:38 p.m. | Last Modified: 2 Feb 2021, 5:38 p.m.

Panel Version: 2.12

- In 3 individuals with AML (including 2 sibs) and LoF variants in MBD4, Sanders et al. 2018 (PMID: 30049810) demonstrated that MBD4-deficient cancers exhibit a unique mutational signature with high burden of CpG>TpG mutations. Note that PMID: 32239153 refer to the same individuals.

The MBD4-related hypermutator phenotype has also been detected in Mbd4 mutant mice (PMID:12417741) and other human cancers such as uveal melanoma and colorectal tumours (PMID: 29760383; 32239153; 31322271).

Created: 2 Feb 2021, 5:27 p.m. | Last Modified: 2 Feb 2021, 5:27 p.m.

Panel Version: 2.11

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Multi-organ tumour predisposition syndrome; Adenomatous colorectal polyposis; Colorectal cancer; Acute myeloid leukemia; Uveal melanoma

Publications

• 12417741
• 30049810
• 32239153
• 35460607

Green List (high evidence)

Sources: Literature

Created: 29 Jan 2021, 11:58 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
AML, colonic polyps, uveal melanoma, glioblastoma

Publications

• PMID: 30049810
• PMID: 29760383
• PMID: 32239153